丙戊酸盐对大鼠海马切片中锥体神经元作用的电生理分析

Electrophysiologic analysis of the actions of valproate on pyramidal neurons in the rat hippocampal slice.

作者信息

Albus H, Williamson R

机构信息

Department of Physiology, Leiden University and the Instituut voor Epilepsiebestrijding, Heemstede, The Netherlands.

出版信息

Epilepsia. 1998 Feb;39(2):124-39. doi: 10.1111/j.1528-1157.1998.tb01350.x.

DOI:10.1111/j.1528-1157.1998.tb01350.x

PMID:9577992

Abstract

PURPOSE

Studies in invertebrates and cultured mammalian neurons suggested that valproate (VPA) mediates its main antiepileptic effect by slowing the recovery from inactivation of voltage-dependent sodium channels. This predicts an effect on the refractory period of the action potential and, consequently, on the bursting behavior of neurons.

METHODS

We investigated this prediction using intracellular and extracellular recording techniques in hippocampal slices prepared from adult rats. The refractory period (RFP) and the ratio of the slopes (SR) of a pair of action potentials were used as indices of the recovery from inactivation of sodium channels. They were measured by injecting a series of paired depolarizing current pulses into CA1 pyramidal neurons.

RESULTS

No significant changes were observed in the RFP or SR measured during a 1-h recording period when VPA was bath-applied (1 mM), or when it was present in the recording electrode (10-50 mM). Lowering the temperature from 34.5 degrees C to 26.4 degrees C resulted in an increase of the RFP by 100% and a decrease of the SR by 40%. However, VPA did not affect any of the measured action potential parameters at this lower temperature. VPA was also without effect on the presynaptic fiber volley of axons recorded extracellularly in the stratum radiatum. The antidromic population spike was unaffected by VPA (2 mM), whereas phenytoin (50 microM) clearly affected this spike in the same slices. The absence of effect of VPA on each of the measured parameters could not be attributed to poor penetration through the slice because bath-applied VPA reduced the frequency of extracellularly recorded spontaneous interictal bursts, induced by bicuculline and elevated K+, within 10 min.

CONCLUSIONS

These findings suggest that at least in the hippocampal slice the drug's principal antiepileptic effect cannot be explained by its action on voltage-dependent sodium channels.

摘要

目的

对无脊椎动物和培养的哺乳动物神经元的研究表明，丙戊酸盐（VPA）通过减缓电压依赖性钠通道失活后的恢复过程来介导其主要抗癫痫作用。这预示着其对动作电位的不应期有影响，进而对神经元的爆发行为产生影响。

方法

我们使用细胞内和细胞外记录技术，对成年大鼠制备的海马切片进行研究，以验证这一预测。不应期（RFP）和一对动作电位的斜率比（SR）被用作钠通道失活后恢复情况的指标。通过向CA1锥体神经元注入一系列成对的去极化电流脉冲来进行测量。

结果

当通过浴槽给药（1 mM）或存在于记录电极中（10 - 50 mM）时，在1小时的记录期内，所测量的RFP或SR均未观察到显著变化。将温度从34.5摄氏度降至26.4摄氏度会导致RFP增加100%，SR降低40%。然而，在这个较低温度下，VPA并未影响所测量的任何动作电位参数。VPA对在放射层细胞外记录的轴突的突触前纤维群峰电位也没有影响。VPA（2 mM）对逆行性群体峰电位没有影响，而苯妥英（50 microM）在同一切片中明显影响了该峰电位。VPA对每个测量参数均无影响，这不能归因于其穿透切片的能力差，因为浴槽给药的VPA在10分钟内降低了由荷包牡丹碱和高钾诱导的细胞外记录的自发性发作间期爆发的频率。